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CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

206500Orig1s000

RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management

RISK EVALUATION AND MITIGATION STRATEGY (REMS) REVIEW

Date: August 25, 2015

Reviewer(s): Felicia Duffy, RN, BSN, MSEd Division of Risk Management Acting Team Leader: Jamie Wilkins Parker, Pharm.D. Division of Risk Management Acting Deputy Reema Mehta, Pharm.D., M.P.H. Division Director: Division of Risk Management Subject: Evaluation to determine if a REMS is necessary Drug Name(s): rolapitant Therapeutic Class: selective competitive antagonist of human /NK1 receptors Dosage and Route: 90 mg tablets Indication: induced nausea and vomiting Application Type/Number: NDA 206500 Applicant/sponsor: Tesaro, Inc. OSE RCM #: 2014-2149

1 Reference ID: 3811205 1 INTRODUCTION The purpose of this review is to document the Division of Risk Management’s (DRISK) evaluation to assess the need for a risk evaluation and mitigation strategy (REMS) for rolapitant hydrochloride tablets, NDA 206500. On September 5, 2014, the Agency received an original NDA from Tesaro, Inc. (Tesaro) for rolapitant. The Sponsor’s proposed indication is for use in combination with other agents in adults for the prevention of (b) (4) delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Tesaro did not include a proposed REMS or risk management plan with the submission. 1.1 BACKGROUND OF CONDITION1,2 Nausea and vomiting are two of the most debilitating side effects of cytotoxic chemotherapy. After administration of highly-emetogenic chemotherapy (HEC) without prophylaxis, >90% of treated patients will experience chemotherapy-induced nausea and vomiting (CINV). Agents that induce an incidence of CINV in 31% to 90% of patients are referred to as moderately- emetogenic chemotherapy (MEC). Active management of CINV reduces patient suffering and increases the likelihood that cancer patients will continue to receive potentially life-extending treatment on schedule and at appropriate doses. There are two described phases of CINV, acute and delayed, which are mediated by neurotransmitter-driven mechanisms, primarily serotonin (5-HT) and neurokinin (NK1). The acute phase, which represents the first 24 hours following chemotherapy, is mediated in part by chemotherapy-induced increases in 5-HT release and activation of 5-HT3 receptors on vagal afferent neurons in the gut. In addition to serotonin, other neurotransmitters are implicated in the etiology of acute CINV, as indicated by a further reduction in the incidence of nausea and vomiting when NK1 receptor antagonists are added to a standard antiemetic regimen that includes a 5-HT3 receptor antagonist. The etiology of the delayed phase of CINV, which occurs 2 to 5 days following the initiation of chemotherapy, involves the release of the neurokinin peptide substance P in the brain. Antiemetic therapy with a corticosteroid and 5-HT3 receptor antagonist alone is minimally effective during the delayed phase of CINV. The combination of NK1 and 5-HT3 receptor antagonists, together with a corticosteroid, provides the greatest preventative effect from CINV. This triplet mitigates risk for CINV across the entire 5-day period following administration of chemotherapy. For patients who cannot tolerate , triplet therapy may not be an option and for these patients, an NK1 receptor antagonist becomes even more important for offering protection from CINV. A variety of treatments are used to prevent CINV. Treatment regimens differ based on the emetogenic potential of the chemotherapeutic agents (i.e., high, medium, low). Table 1 below describes the typical treatment regimens used to prevent CINV based on the emetogenic potential of the chemotherapeutic agent(s).

1 Tesaro. Clinical Overview for Varubi (rolapitant hydrochloride), received September 5, 2014. Supplement 000/Sequence 0000.

2 Tesaro. Summary of Clinical Safety for Varubi (rolapitant hydrochloride), received September 5, 2014. Supplement 000/Sequence 0000.

2 Reference ID: 3811205 Table 1. Adult patients exposed to emetogenic chemotherapeutic agents are treated with the following to prevent CINV3:

Emetic risk and effects Therapy Recommended dosage Emetic risk: high 5-HT3 receptor antagonists AND 100 mg orally or 100 dexamethasone orally or IV AND mg IV or 1.8 mg/mg IV substance P neurokinin-1 (NK-1)- 2 mg orally or 1 mg 5-HT3 receptor antagonists: receptor antagonist ( or IV or 0.01 mg/kg IV or 34.3 mg common side effects – ) transdermal patch constipation, headache, asthenia; serious side effects: 16 – 24 mg orally or hypersensitivity (W&P); QT 8 – 12 mg IV (maximum 32 mg) prolongation (adverse reactions) 0.25 mg IV NK-1 receptor antagonists: Dexamethasone 12 mg orally common side effects - alopecia, anorexia, asthenia/fatigue, Aprepitant 125 mg orally or constipation, diarrhea, headache, hiccups, nausea Fosaprepitant 115 mg IV /palonosetron 300mg/0.5mg orally Emetic risk: moderate 5-HT3 receptor antagonists AND Dolasetron 100 mg orally or 100 dexamethasone orally or IV AND mg IV or 1.8 mg/mg IV aprepitant or fosaprepitant Granisetron 2 mg orally or 1 mg IV or 0.01 mg/kg IV or 34.3 mg transdermal patch Ondansetron 16 – 24 mg orally or 8 – 12 mg IV (maximum 32 mg) Palonosetron 0.25 mg IV or Palonosetron 0.5 mg orally Dexamethasone 8 - 12 mg orally or IV Aprepitant 125 mg orally or Fosaprepitant 115 mg IV Emetic risk: low Dexamethasone Dexamethasone 8 - 12 mg orally or IV Emetic risk: minimal None N/A

NK-1 receptor antagonists are associated with alopecia, anorexia, asthenia/fatigue, constipation, diarrhea, headache, hiccups, nausea and may cause clinically significant drug-drug interactions with warfarin and oral contraceptives in light of its inhibition of the CYP3A4 isoenzyme.

3 Barbara Wells, et al. Dosage Recommendations for CINV for Adult Patients, Chapter 27, Nausea and Vomiting, Pharmacotherapy Handbook, 2012.

3 Reference ID: 3811205

 Johnson, A. DGIEP Mid-cycle Meeting slides for Rolapitant (NDA 206500), dated February 3, 2015.  Chung M. DGIEP Mid-cycle Communication to Tessaro Inc. for Rolapitant (NDA 206500), dated March 13, 2015.  Johnson, A. DGIEP Clinical Review for Rolapitant (NDA 206500), dated May 5, 2015.  Tesaro Inc., Draft Prescribing Information for Rolapitant (NDA 206500), received July 25, 2015.

3 RESULTS OF REVIEW 3.1 OVERVIEW OF CLINICAL PROGRAM

The core development program to support efficacy of rolapitant for the prevention of (b) (4) delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy is based on three clinical studies (Study P04832, P04833, and P04834). For all 3 studies, the primary efficacy endpoint was complete response (CR) defined as having no emesis and no rescue medication use in the delayed phase (>24-120 hours) following the administration of HEC or MEC during the first cycle of chemotherapy. No emesis was defined as no vomiting, wretching or dry heaving. Additional details regarding the studies is as follows:  Studies P04832 and P04833: These HEC studies were identical with the exception of the location of the study sites. The studies were global, multicenter, randomized, parallel- group, double-blind, and active-controlled studies. The primary objective of the studies was to determine whether administration of rolapitant with a 5-HT3 receptor antagonist (granisetron) and dexamethasone improves protection from CINV in the delayed phase (>24 to 120 hours) compared to administration of placebo with a 5-HT3 receptor antagonist and dexamethasone in subjects receiving HEC. All subjects received a single dose of rolapitant 200 mg or placebo 1 to 2 hours prior to administration of the first chemotherapeutic agent on Day 1. In Study P04832 and P04833, per DGIEP, the CR rate in the delayed phase was statistically significantly higher in the rolapitant 200 mg compared to the placebo group. The control rate seen in rolapitant patients was 72.7% and 70.1%, respectively; while the control rate seen in placebo patients was 58.4% and 61.9%, respectively.

 Study P04834: This study was a global, multicenter, randomized, parallel-group, double- blind, active-controlled study designed to determine whether administration of rolapitant with a 5-HT3 receptor antagonist and dexamethasone improves CINV in the delayed phase (>24 to 120 hours) compared with administration of placebo with 5-HT3 receptor antagonist (granisetron) and dexamethasone in subjects receiving MEC. The dose and timing of receipt of rolapitant or placebo (i.e., 1-2 hours prior to the initiation of chemotherapy on Day 1) was the same in this study as in studies P04832 and P0433. Per DGIEP, the CR rate for patients taking rolapitant in the delayed phase was 71.3% compared with a 61.6% complete response rate seen in placebo patients, p<0.001.

5 Reference ID: 3811205

In the clinical trials, rolapitant was found to be more efficacious as compared to placebo for the prevention of CINV during the delayed phase, and will be approved with the indication for use in combination with other antiemetic agents in adults for the preventin of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including but not limited to HEC. Rolapitant was associated with a low incidence of SAEs and non-serious adverse events. Most deaths were associated with comorbidities associated with the patient’s cancer diagnosis or adverse events from a patient’s chemotherapy regimen. Furthermore, the observed safety profile in the clinical studies for rolapitant was consistent with the known safety profile for the drug class. Therefore, DRISK has determined that a REMS is not necessary to ensure the benefits of rolapitant outweigh the risks.

5 CONCLUSION In conclusion, risk mitigation measures beyond professional labeling are not necessary for rolapitant. Rolapitant has proven efficacy and safety for its use in combination with other antiemetic agents for the prevention of delayed nausea and vomiting associated with initial and repeat course of emetogenic cancer chemotherapy. Thus, the benefit-risk profile for rolapitant is acceptable and the risks can be adequately communicated through professional labeling. Should DGIEP have any concerns or questions, feel that a REMS may be warranted for this product, or if new safety information becomes available, please send a consult to DRISK.

7 Reference ID: 3811205 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------JAMIE C WILKINS PARKER 08/25/2015

REEMA J MEHTA 08/26/2015 I concur.

Reference ID: 3811205